Phosphorylated Proteins and Control over Apatite Nucleation, Crystal Growth, and Inhibition

George, Anne; Veis, Arthur

doi:10.1021/cr0782729

Cited by 656 publications

(661 citation statements)

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“…It is possible that Fam20C regulates FGF23 not only through direct mechanisms, as our results suggest, but also through emerging, indirect pathways. In this regard, we have shown that DMP1, a highly phosphorylated extracellular matrix protein critical for proper mineralization of bone (46), is a substrate for Fam20C (3,4). Inactivating mutations in DMP1 result in autosomal recessive hypophosphatemic rickets, and Dmp1 KO mice share many phenotypic similarities with those of Fam20C-deficient animals, including elevated FGF23 (13,22).…”

Section: Discussionmentioning

confidence: 98%

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

Tagliabracci¹,

Engel²,

Wiley³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

278

252

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The family with sequence similarity 20, member C (Fam20C) has recently been identified as the Golgi casein kinase. Fam20C phosphorylates secreted proteins on Ser-x-Glu/pSer motifs and loss-of-function mutations in the kinase cause Raine syndrome, an often-fatal osteosclerotic bone dysplasia. Fam20C is potentially an upstream regulator of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), because humans with FAM20C mutations and Fam20C KO mice develop hypophosphatemia due to an increase in full-length, biologically active FGF23. However, the mechanism by which Fam20C regulates FGF23 is unknown. Here we show that Fam20C directly phosphorylates FGF23 on Ser 180 , within the FGF23 R 176 XXR 179 /S 180 AE subtilisin-like proprotein convertase motif. This phosphorylation event inhibits O-glycosylation of FGF23 by polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3), and promotes FGF23 cleavage and inactivation by the subtilisin-like proprotein convertase furin. Collectively, our results provide a molecular mechanism by which FGF23 is dynamically regulated by phosphorylation, glycosylation, and proteolysis. Furthermore, our findings suggest that cross-talk between phosphorylation and O-glycosylation of proteins in the secretory pathway may be an important mechanism by which secreted proteins are regulated.phosphate homeostasis | rickets | Fam20 | familial tumoral calcinosis | chronic kidney disease P rotein kinases are evolutionarily conserved enzymes that regulate numerous cellular processes by transferring a molecule of phosphate from ATP to target substrates (1, 2). The vast majority of theses enzymes function within the nucleus and cytosol. In contrast, there are several examples of phosphorylated proteins that are secreted from the cell, which raises the question: What are the kinases that phosphorylate these secreted phosphoproteins? We recently identified a small family of secretory pathway kinases that phosphorylate secreted proteins and proteoglycans (3). These enzymes have N-terminal signal sequences that direct them to the lumen of the endoplasmic reticulum, where they encounter the proteins or proteoglycans that they phosphorylate. One member of this atypical kinase family is the family with sequence similarity 20, member C (Fam20C), which phosphorylates secreted proteins on Ser(S)-xGlu(E)/pSer(pS) (S-x-E/pS) motifs (3, 4). Because Fam20C localizes within the secretory pathway and the vast majority of secreted phosphoproteins are phosphorylated on S-x-E/pS motifs, Fam20C has been proposed to play a major role in the generation of the secreted phosphoproteome (5-7). For example, ∼75% of human serum and cerebrospinal fluid phosphoproteins are phosphorylated on S-x-E/pS motifs (8, 9). This includes proteins important for tooth and bone formation, as well as numerous hormones. In most cases, the functional importance of these phosphorylation events is unknown.Loss-of-function mutations in the human FAM20C gene cause Raine syndrome, an often-fatal osteosclerotic bone dysplasia (10, 11)....

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Section: Discussionmentioning

confidence: 98%

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

Tagliabracci¹,

Engel²,

Wiley³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

278

252

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“…Most vertebrate bodily fluids are supersaturated with respect to both hydroxyapatite and amorphous calcium phosphate (ACP), where some intrinsically disordered proteins such as caseins and osteopontin (OPN) form stable or metastable complexes with calcium phosphate (Holt et al 2014, George andVeis 2008). The best characterised example is the casein micelle of milk, which contains hundreds of nanoclusters of calcium phosphate in a single colloidal casein micelle of ~100 nm radius (see also section 2.2).…”

Section: Introductionmentioning

confidence: 99%

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

et al. 2016

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There are abundant examples of nanoclusters and inorganic microcrystals in biology.Their study under physiologically relevant conditions remains challenging due to their instability, the requirements of sample preparation and other intrinsic limitations of the techniques used. Advantages of using neutron diffraction and contrast matching to characterize biomaterials are highlighted in this article. We have applied these methods and complementary techniques to search for long-range order within nanoclusters of calcium phosphate sequestered by bovine phosphopeptides, derived from osteopontin or casein. Hydrated and dried samples with different nanocluster radii were analyzed and compared to samples of known calcium phosphate phases. The absence of a distinct diffraction pattern from the nanoclusters is consistent with the presence of amorphous calcium phosphate structure.

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“…It is present in the extracellular matrices of bone and teeth, but not in nonmineralized tissues 27 . Dentin matrix protein (DMP1) likewise is important in promoting extracellular matrix mineralization, as shown by mouse models and patients with deletion/mutations in the gene encoding DMP1 having autosomal recessive hypophosphatemic rickets (ARHR) characterized by osteomalacia.…”

Section: General Inhibition Selective Promotion and Selective Inhibimentioning

confidence: 99%

“…Defects in the gene encoding MGP in humans (causing Singleton-Merten syndrome, Keutel syndrome) lead to catastrophic mineralization that causes fatal rupture of the aorta and/or premature growth plate fusion in long bones, and joint ankylosis 35 . For other mineralization inhibitors, such as Matrix Extracellular Phosphoglycoprotein (MEPE) and the peptide Acidic Serine and Aspartate-Rich Motif (ASARM) found in SIBLING proteins, the reader can be referred to excellent recent reviews 27,[37][38][39] . 40 …”

Section: General Inhibition Selective Promotion and Selective Inhibimentioning

confidence: 99%

“…Most mineralization inhibitors, that may play a dual role as mineral nucleators under certain circumstances 27 , are abundant in physiologically mineralized tissues. Redundant inhibitors are incorporated into bone for a strategic reason -mineralization has to be confined to a narrow range of about 65-70% (weight) 49 .…”

Section: Biomechanical Implications Of Inhibition and Promotion Of MImentioning

confidence: 99%

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A materials science vision of extracellular matrix mineralization

et al. 2016

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From an engineering perspective, skeletal tissues are remarkable structures in that they are lightweight, stiff and tough, yet produced at ambient conditions. The biomechanical success of skeletal tissues is largely attributable to the process of biomineralization -a tightly regulated, cell-driven formation of billions of inorganic nanocrystals formed from ions found abundantly in body fluids. In this Review, we discuss nature's strategies to produce and sustain appropriate biomechanical properties in mineralizing (by promotion of mineralization) and nonmineralizing (by inhibition of mineralization) tissues. We review how perturbations of biomineralization are controlled over a continuum which spans from the desirable (or defective in disease) mineralization of the skeleton, to pathological cardiovascular mineralization, and to mineralization of bioengineered constructs. A materials science vision of mineralization is presented with an emphasis on the micro-and nanostructure of mineralized tissues recently revealed by state-of-the-art analytical methods, and on how biomineralization-inspired designs are impacting the field of synthetic materials. Web summaryComplex mechanisms are at play in the biomineralization of skeletal tissues and in patholological calcification in the cardiovascular system. In this Review, the physiochemical and biomechanical properties of mineralized tissues, both physiologic and pathophysiologic, and analytical methods to elucidate their finer structure are discussed.

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Phosphorylated Proteins and Control over Apatite Nucleation, Crystal Growth, and Inhibition

Cited by 656 publications

References 281 publications

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

A materials science vision of extracellular matrix mineralization

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